Background: Midbrain dopaminergic neurons (MDN) represent 0.0005% of the brain's neuronal population and mediate cognition, food intake, and metabolism. MDN are also posited to underlay the neurobiological dysfunction of schizophrenia (SCZ), a severe neuropsychiatric disorder that is characterized by psychosis as well as multifactorial medical co-morbidities, including metabolic disease, contributing to markedly increased morbidity and mortality. Paradoxically, however, the genetic risk sequences of psychosis and traits associated with metabolic disease, such as body mass, show very limited overlap. Methods: We investigated the genomic interaction of SCZ with medical conditions and traits, including body mass index (BMI), by exploring the MDN's "spatial genome," including chromosomal contact landscapes as a critical layer of cell type-specific epigenomic regulation. Low-input Hi-C protocols were applied to 5-10 × 10 3 dopaminergic and other cell-specific nuclei collected by fluorescence-activated nuclei sorting from the adult human midbrain. Results: The Hi-C-reconstructed MDN spatial genome revealed 11 "Euclidean hot spots" of clustered chromatin domains harboring risk sequences for SCZ and elevated BMI. Inter-and intra-chromosomal contacts interconnecting SCZ and BMI risk sequences showed massive enrichment for brain-specific expression quantitative trait loci (eQTL), with gene ontologies, regulatory motifs and proteomic interactions related to adipogenesis and lipid regulation, dopaminergic neurogenesis and neuronal connectivity, and reward-and addiction-related pathways. Conclusions: We uncovered shared nuclear topographies of cognitive and metabolic risk variants. More broadly, our PsychENCODE sponsored Hi-C study offers a novel genomic approach for the study of psychiatric and medical co-morbidities constrained by limited overlap of their respective genetic risk architectures on the linear genome.
Background: The objective of this analysis was to systematically review studies employing wearable technology in patients with dementia by quantifying differences in digitally captured physiological endpoints.Methods: This systematic review and meta-analysis was based on web searches of Cochrane Database, PsycInfo, Pubmed, Embase, and IEEE between October 25–31st, 2017. Observational studies providing physiological data measured by wearable technology on participants with dementia with a mean age ≥50. Data were extracted according to PRISMA guidelines and methodological quality assessed independently using Downs and Black criteria. Standardized mean differences between cases and controls were estimated using random-effects models.Results: Forty-eight studies from 18,456 screened abstracts (Dementia: n = 2,516, Control: n = 1,224) met inclusion criteria for the systematic review. Nineteen of these studies were included in one or multiple meta-analyses (Dementia: n = 617, Control: n = 406). Participants with dementia demonstrated lower levels of daily activity (standardized mean difference (SMD), −1.60; 95% CI, −2.66 to −0.55), decreased sleep efficiency (SMD, −0.52; 95% CI, −0.89 to −0.16), and greater intradaily circadian variability (SMD, 0.46; 95% CI, 0.27 to 0.65) than controls, among other measures. Statistical between-study heterogeneity was observed, possibly due to variation in testing duration, device type or patient setting.Conclusions and Relevance: Digitally captured data using wearable devices revealed that adults with dementia were less active, demonstrated increased fragmentation of their sleep-wake cycle and a loss of typical diurnal variation in circadian rhythm as compared to controls.
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